The major objectives of this project are to define the role of type I interferons (IFN-alpha/beta) in the pathogenesis of disease in a mouse model of systemic lupus erythematosus (SLE) and to provide additional evidence to target these cytokines in this disease. Studies in SLE patients with active disease have demonstrated elevated levels of IFN-alpha/beta as well as changes in gene expression and cell phenotypes that reflect this increased production. Furthermore, studies suggest that lupus and other types of autoimmune disease can be induced or exacerbated by administration of IFN-alpha/beta. A focus on IFN-alpha/beta in lupus is additionally supported by studies from the investigators' laboratories pointing to the interferon-inducible gene, Ifi202, in the genetic contribution to a mouse model of lupus, and studies showing that IFN-alpha/beta directly protect T cells from undergoing activation-induced cell death. It is hypothesized that IFN-alpha/beta are critically involved in the pathogenesis of lupus because of direct effects on particular cell types of the immune system, and that Ifi202 partially underlies the lupus-promoting effects of IFN-alpha/beta. In the current application, we investigate the effects of IFN-alpha/beta on the development and exacerbation of mouse lupus and the mechanisms for these effects. In particular, studies with IFN-alpha/beta receptor deficient mice will determine whether IFN-alpha/beta are required for the development of disease and whether IFN-alpha/beta can enhance disease expression in certain mouse models of lupus. Using bone marrow chimeras and mixed-chimeras, studies will determine whether the effects of IFN-alpha/beta on lupus are mediated through bone marrow derived cells and will define the cell types involved. Separate studies of cellular mechanisms will determine whether IFN-alpha/beta prevents activation-induced apoptosis of B cells or T cells and whether Ifi202 is involved in this effect, and will test whether effects on dendritic cells underlie the role of IFN-alpha/beta in lupus. A final group of experiments will determine whether disease expression can be prevented and suppressed through inhibition of IFN-alpha/beta function. Together, the studies in this application should provide new insight into the pathogenesis of lupus and provide the basis for a new therapeutic target in SLE.